Fluoxetine Decreases Phagocytic Function via REV-ERBα in Microglia

Abstract

Although uoxetine (FLX) is a commonly used drug in psychiatric disorders, such as major depressive disorder (MDD), anxiety disorder, panic disorder, and obsessive-compulsive disorder (OCD), the mechanism by which FLX exerts its therapeutic effect is not completely understood. In this study, we aimed to determine the possible mechanism by which FLX focuses on microglial phagocytosis. FLX reduced phagocytic function in BV2 cells and increased REV-ERBα among circadian genes without affecting other microglia-related genes, such as in ammation and phagocytosis. Although FLX did not change BMAL1 protein levels, it restricted the nucleocytoplasmic transport (NCT) of BMAL1, leading to its cytosolic accumulation. REV-ERBα antagonist SR8278 rescued the decreased phagocytic and restricted NCT of BMAL1. We also found that REV-ERBα mediates the effect of FLX via the inhibition of phospho-ERK (pERK). The ERK inhibitor FR180204 was su cient to reduce phagocytic function in BV2 cells and restrict the NCT of BMAL1. These results were recapitulated in the primary microglia. In conclusion, we propose that FLX decreases phagocytic function and restricts BMAL1 NCT via REV-ERB. In addition, ERK inhibition mimics the effects of FLX on microglia.

Roles of microglia in adult hippocampal neurogenesis in depression and their therapeutics

“…Synapses interconnect neurons into networks that transmit neurotransmitters and mediate neuronal signaling, which contains pre-and postsynaptic separated by the synaptic cleft. Preclinical and clinical evidence suggests activated microglia in depressed animals and humans may aberrantly phagocytose neuronal synapses, resulting in synaptic dysfunction and depressive symptoms ( 78 , 79 ). Preclinical studies in mouse models of depression have reported increased microglial phagocytosis of synapses in microglia-neuron contact areas ( 80 ).…”